EP0440341B1 - EFA compositions and therapy - Google Patents
EFA compositions and therapy Download PDFInfo
- Publication number
- EP0440341B1 EP0440341B1 EP91300234A EP91300234A EP0440341B1 EP 0440341 B1 EP0440341 B1 EP 0440341B1 EP 91300234 A EP91300234 A EP 91300234A EP 91300234 A EP91300234 A EP 91300234A EP 0440341 B1 EP0440341 B1 EP 0440341B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- gla
- selenium
- acid
- dgla
- acids
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 239000000203 mixture Substances 0.000 title description 7
- 238000002560 therapeutic procedure Methods 0.000 title description 2
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 claims abstract description 34
- 229910052711 selenium Inorganic materials 0.000 claims abstract description 30
- 239000011669 selenium Substances 0.000 claims abstract description 30
- HOBAELRKJCKHQD-UHFFFAOYSA-N (8Z,11Z,14Z)-8,11,14-eicosatrienoic acid Natural products CCCCCC=CCC=CCC=CCCCCCCC(O)=O HOBAELRKJCKHQD-UHFFFAOYSA-N 0.000 claims abstract description 24
- HOBAELRKJCKHQD-QNEBEIHSSA-N dihomo-γ-linolenic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/CCCCCCC(O)=O HOBAELRKJCKHQD-QNEBEIHSSA-N 0.000 claims abstract description 24
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000011701 zinc Substances 0.000 claims abstract description 17
- 229910052725 zinc Inorganic materials 0.000 claims abstract description 17
- 235000021298 Dihomo-γ-linolenic acid Nutrition 0.000 claims description 23
- 206010012289 Dementia Diseases 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 6
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 5
- 229930195729 fatty acid Natural products 0.000 claims description 5
- 239000000194 fatty acid Substances 0.000 claims description 5
- 150000004665 fatty acids Chemical class 0.000 claims description 5
- 239000011149 active material Substances 0.000 claims description 2
- 238000009109 curative therapy Methods 0.000 claims description 2
- 238000009117 preventive therapy Methods 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 6
- 235000020664 gamma-linolenic acid Nutrition 0.000 description 38
- VZCCETWTMQHEPK-QNEBEIHSSA-N gamma-linolenic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/CCCCC(O)=O VZCCETWTMQHEPK-QNEBEIHSSA-N 0.000 description 37
- VZCCETWTMQHEPK-UHFFFAOYSA-N gamma-Linolensaeure Natural products CCCCCC=CCC=CCC=CCCCCC(O)=O VZCCETWTMQHEPK-UHFFFAOYSA-N 0.000 description 35
- 229960002733 gamolenic acid Drugs 0.000 description 35
- 239000002253 acid Substances 0.000 description 27
- 229940091258 selenium supplement Drugs 0.000 description 26
- 150000007513 acids Chemical class 0.000 description 20
- 235000004626 essential fatty acids Nutrition 0.000 description 17
- 239000003921 oil Substances 0.000 description 14
- 235000019198 oils Nutrition 0.000 description 14
- MBMBGCFOFBJSGT-KUBAVDMBSA-N all-cis-docosa-4,7,10,13,16,19-hexaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCC(O)=O MBMBGCFOFBJSGT-KUBAVDMBSA-N 0.000 description 12
- 238000011282 treatment Methods 0.000 description 9
- DTOSIQBPPRVQHS-PDBXOOCHSA-N alpha-linolenic acid Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCC(O)=O DTOSIQBPPRVQHS-PDBXOOCHSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- OYHQOLUKZRVURQ-HZJYTTRNSA-N Linoleic acid Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(O)=O OYHQOLUKZRVURQ-HZJYTTRNSA-N 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- JAZBEHYOTPTENJ-JLNKQSITSA-N all-cis-5,8,11,14,17-icosapentaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O JAZBEHYOTPTENJ-JLNKQSITSA-N 0.000 description 6
- 235000020661 alpha-linolenic acid Nutrition 0.000 description 6
- BVTBRVFYZUCAKH-UHFFFAOYSA-L disodium selenite Chemical compound [Na+].[Na+].[O-][Se]([O-])=O BVTBRVFYZUCAKH-UHFFFAOYSA-L 0.000 description 6
- 235000020673 eicosapentaenoic acid Nutrition 0.000 description 6
- 229960005135 eicosapentaenoic acid Drugs 0.000 description 6
- JAZBEHYOTPTENJ-UHFFFAOYSA-N eicosapentaenoic acid Natural products CCC=CCC=CCC=CCC=CCC=CCCCC(O)=O JAZBEHYOTPTENJ-UHFFFAOYSA-N 0.000 description 6
- 235000020778 linoleic acid Nutrition 0.000 description 6
- 229960001471 sodium selenite Drugs 0.000 description 6
- 235000015921 sodium selenite Nutrition 0.000 description 6
- 239000011781 sodium selenite Substances 0.000 description 6
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 5
- 210000004556 brain Anatomy 0.000 description 5
- 235000005911 diet Nutrition 0.000 description 5
- 230000000378 dietary effect Effects 0.000 description 5
- 235000020669 docosahexaenoic acid Nutrition 0.000 description 5
- 239000007903 gelatin capsule Substances 0.000 description 5
- OYHQOLUKZRVURQ-IXWMQOLASA-N linoleic acid Natural products CCCCC\C=C/C\C=C\CCCCCCCC(O)=O OYHQOLUKZRVURQ-IXWMQOLASA-N 0.000 description 5
- 229960004488 linolenic acid Drugs 0.000 description 5
- 230000003647 oxidation Effects 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 241000219925 Oenothera Species 0.000 description 4
- RJFAYQIBOAGBLC-BYPYZUCNSA-N Selenium-L-methionine Chemical compound C[Se]CC[C@H](N)C(O)=O RJFAYQIBOAGBLC-BYPYZUCNSA-N 0.000 description 4
- RJFAYQIBOAGBLC-UHFFFAOYSA-N Selenomethionine Natural products C[Se]CCC(N)C(O)=O RJFAYQIBOAGBLC-UHFFFAOYSA-N 0.000 description 4
- 229940090949 docosahexaenoic acid Drugs 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 125000005456 glyceride group Chemical group 0.000 description 4
- 230000037361 pathway Effects 0.000 description 4
- 229960002718 selenomethionine Drugs 0.000 description 4
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 4
- 240000004355 Borago officinalis Species 0.000 description 3
- OPGOLNDOMSBSCW-CLNHMMGSSA-N Fursultiamine hydrochloride Chemical compound Cl.C1CCOC1CSSC(\CCO)=C(/C)N(C=O)CC1=CN=C(C)N=C1N OPGOLNDOMSBSCW-CLNHMMGSSA-N 0.000 description 3
- WHMDKBIGKVEYHS-IYEMJOQQSA-L Zinc gluconate Chemical compound [Zn+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O WHMDKBIGKVEYHS-IYEMJOQQSA-L 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 235000008524 evening primrose extract Nutrition 0.000 description 3
- 238000000855 fermentation Methods 0.000 description 3
- 230000004151 fermentation Effects 0.000 description 3
- 230000002538 fungal effect Effects 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 150000003904 phospholipids Chemical class 0.000 description 3
- 239000000902 placebo Substances 0.000 description 3
- 229940068196 placebo Drugs 0.000 description 3
- JIWBIWFOSCKQMA-UHFFFAOYSA-N stearidonic acid Natural products CCC=CCC=CCC=CCC=CCCCCC(O)=O JIWBIWFOSCKQMA-UHFFFAOYSA-N 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 235000011478 zinc gluconate Nutrition 0.000 description 3
- 239000011670 zinc gluconate Substances 0.000 description 3
- 229960000306 zinc gluconate Drugs 0.000 description 3
- 235000009529 zinc sulphate Nutrition 0.000 description 3
- 239000011686 zinc sulphate Substances 0.000 description 3
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- 235000007689 Borago officinalis Nutrition 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- 208000005314 Multi-Infarct Dementia Diseases 0.000 description 2
- 235000004496 Oenothera biennis Nutrition 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 201000004810 Vascular dementia Diseases 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 235000015872 dietary supplement Nutrition 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 229940089020 evening primrose oil Drugs 0.000 description 2
- 239000010475 evening primrose oil Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- KQQKGWQCNNTQJW-UHFFFAOYSA-N linolenic acid Natural products CC=CCCC=CCC=CCCCCCCCC(O)=O KQQKGWQCNNTQJW-UHFFFAOYSA-N 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 210000002569 neuron Anatomy 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 150000003626 triacylglycerols Chemical class 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 2
- DVSZKTAMJJTWFG-SKCDLICFSA-N (2e,4e,6e,8e,10e,12e)-docosa-2,4,6,8,10,12-hexaenoic acid Chemical compound CCCCCCCCC\C=C\C=C\C=C\C=C\C=C\C=C\C(O)=O DVSZKTAMJJTWFG-SKCDLICFSA-N 0.000 description 1
- VMSLCPKYRPDHLN-UHFFFAOYSA-N (R)-Humulone Chemical compound CC(C)CC(=O)C1=C(O)C(CC=C(C)C)=C(O)C(O)(CC=C(C)C)C1=O VMSLCPKYRPDHLN-UHFFFAOYSA-N 0.000 description 1
- GZJLLYHBALOKEX-UHFFFAOYSA-N 6-Ketone, O18-Me-Ussuriedine Natural products CC=CCC=CCC=CCC=CCC=CCC=CCCCC(O)=O GZJLLYHBALOKEX-UHFFFAOYSA-N 0.000 description 1
- OYHQOLUKZRVURQ-UHFFFAOYSA-N 9,12-Octadecadienoic Acid Chemical compound CCCCCC=CCC=CCCCCCCCC(O)=O OYHQOLUKZRVURQ-UHFFFAOYSA-N 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 239000004261 Ascorbyl stearate Substances 0.000 description 1
- 235000021357 Behenic acid Nutrition 0.000 description 1
- 206010013710 Drug interaction Diseases 0.000 description 1
- 102000006587 Glutathione peroxidase Human genes 0.000 description 1
- 108700016172 Glutathione peroxidases Proteins 0.000 description 1
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 description 1
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- 240000008916 Oenothera biennis Species 0.000 description 1
- 241000179990 Oenothera lamarckiana Species 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- 235000011483 Ribes Nutrition 0.000 description 1
- 241000220483 Ribes Species 0.000 description 1
- 240000001890 Ribes hudsonianum Species 0.000 description 1
- 235000016954 Ribes hudsonianum Nutrition 0.000 description 1
- 235000001466 Ribes nigrum Nutrition 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 230000037374 absorbed through the skin Effects 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000002547 anomalous effect Effects 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 235000010385 ascorbyl palmitate Nutrition 0.000 description 1
- 235000019276 ascorbyl stearate Nutrition 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000012159 carrier gas Substances 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000010411 cooking Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- KAUVQQXNCKESLC-UHFFFAOYSA-N docosahexaenoic acid (DHA) Natural products COC(=O)C(C)NOCC1=CC=CC=C1 KAUVQQXNCKESLC-UHFFFAOYSA-N 0.000 description 1
- UKMSUNONTOPOIO-UHFFFAOYSA-N docosanoic acid Chemical class CCCCCCCCCCCCCCCCCCCCCC(O)=O UKMSUNONTOPOIO-UHFFFAOYSA-N 0.000 description 1
- 229940045761 evening primrose extract Drugs 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 235000019387 fatty acid methyl ester Nutrition 0.000 description 1
- 235000021323 fish oil Nutrition 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 229940066963 gamma-linolenate Drugs 0.000 description 1
- 238000001030 gas--liquid chromatography Methods 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229940049918 linoleate Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 235000013310 margarine Nutrition 0.000 description 1
- 239000003264 margarine Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- JBXYCUKPDAAYAS-UHFFFAOYSA-N methanol;trifluoroborane Chemical compound OC.FB(F)F JBXYCUKPDAAYAS-UHFFFAOYSA-N 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 235000020777 polyunsaturated fatty acids Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 238000009790 rate-determining step (RDS) Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 210000000614 rib Anatomy 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 230000000698 schizophrenic effect Effects 0.000 description 1
- 229940000207 selenious acid Drugs 0.000 description 1
- 235000011649 selenium Nutrition 0.000 description 1
- MCAHWIHFGHIESP-UHFFFAOYSA-N selenous acid Chemical compound O[Se](O)=O MCAHWIHFGHIESP-UHFFFAOYSA-N 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 230000003019 stabilising effect Effects 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/04—Sulfur, selenium or tellurium; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/28—Compounds containing heavy metals
- A61K31/315—Zinc compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/30—Zinc; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/56—Materials from animals other than mammals
- A61K35/60—Fish, e.g. seahorses; Fish eggs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/06—Fungi, e.g. yeasts
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Definitions
- the invention relates to pharmaceutical compositions of essential fatty acids (EFAs) and treatment of disease therewith.
- EFAs essential fatty acids
- Dementia and depression are common psychiatric disorders. They frequently occur together in the same patient.
- Dementia can be caused by a variety of underlying disorders, the most important being Alzheimer's disease, multi-infarct dementia, and infections with certain viruses or virus-like agents.
- the cause of Alzheimer's disease is unknown but there is loss of nerve cells in key areas of the brain.
- multi-infarct dementia cell death follows reduced oxygen and blood flow as a consequence of multiple blockages of small arteries. There are no known satisfactory treatments for dementia of any type.
- the acids which in nature are of the all-cis configuration, are systematically named as derivatives of the corresponding octadecanoic, eicosanoic or docosanoic acids, e.g. delta-9,12-octadecadienoic acid or delta-4,7,10,13,16,19-docosahexaenoic acid, but numerical designations such as, correspondingly, 18:2 n-6 or 22: 6 n-3 are convenient.
- n-3 series only 18:3 n-3 has a commonly used trivial name, alpha-linolenic acid, though the name stearidonic acid is coming into use for the 18:4 n-3 acid and the names eicosapentaenoic acid and docosahexanenoic acid as such are also used.
- the alpha isomer of linolenic acid was characterised earlier than gamma-linolenic acid and reference in the literature simply to linolenic acid, especially in the earlier literature, is to the alpha-acid.
- the cell membranes of nerve cells in the brain are rich in EFAs derived as above from dietary linoleic acid (LA) and alpha-linolenic acid (ALA).
- LA dietary linoleic acid
- ALA alpha-linolenic acid
- the brain contains very little linoleic acid and alpha-linolenic acid: almost all its EFAs are in the form of derivatives of the dietary acids arising from initial 6-desaturation, and are required for normal membrane structure and normal function. Since the 6-desaturation of linoleic acid and alpha-linolenic acid is a slow, rate-limiting step which can be interfered with by many factors, administration of these acids is not a good way to elevate brain EFA levels.
- GLA gamma-linolenic acid
- DGLA dihomo-gamma-linolenic acid
- EPA eicosapentaenoic acid
- DHA docosa-hexaenoic acid
- GLA gamma-linolenic acid
- evening primrose oil 6 g/day containing about 500 mg of GLA
- DGLA gamma-linolenic acid
- These patients were also given zinc sulphate (200 mg/day) and sodium selenite (2 mg/day) each mg containing about 457 microg elemental selenium).
- the other half of the patients were given placebo corresponding to the GLA, zinc and selenium.
- Selenium can inhibit the oxidation of EFAs and also, as a component of the enzyme glutathione peroxidase, help to eliminate any harmful peroxides which may be formed by EFA oxidation. There are therefore strong reasons for combining GLA and DGLA and selenium.
- the GLA and/or DGLA will raise the levels of the appropriate EFAs at important sites in the body: the selenium will inhibit the oxidation of these important compounds and will also help to remove any oxidation products which happen to be formed.
- This inter-action between GLA/DGLA and selenium is in no way dependent on the presence of zinc and will occur entirely independently of zinc. Zinc may improve the responses to GLA and selenium even further by increasing the availability of the GLA or DGLA.
- the patients were randomly allocated to the active and placebo groups and the trial was conducted on a double-blind basis.
- the patients were treated for twenty weeks and the tests were performed before treatment started and at the end of treatment.
- composition according to the invention may be used in the treatment or prevention of dementia and/or depression.
- the GLA or DGLA may be used at 1 mg to 20 g/day, preferably 50 mg to 4 g and very preferably 200 mg to 2 g. Like amounts of n-3 EFAs, where present, may be used. GLA can be synthesised but it is usually derived from natural oils such as those of the evening primrose, blackcurrant or borage, or the storage oils of various fungi. GLA and other EFAs can be administered in any biologically assimilable form, such as the free acid, salt, ester, amide, phospholipid or natural or synthetic tri-glycerides. It can be administered in any convenient way, eg. orally, parenterally, topically or rectally, as can the compositions as a whole. DGLA as such is not readily available, but fungal sources are known and chemical synthesis is possible; amounts for administration are as for GLA.
- the selenium may be used at 1 to 10,000 microg per day, (elemental selenium basis) preferably 50 to 2000 microg/day, very preferably 200 to 1000 microg/ day.
- the selenium too can be administered in any convenient way, i.e. orally, parenterally, rectally or topically in any biologically assimilable form.
- Possible forms include sodium selenite, selenious acid, selenomethionine and selenium yeast (yeast grown in a bioavailable selenium containing environment).
- the GLA and selenium, and the zinc and n-3 EFAs when used may be incorporated in the same formulation for ease of administration or may be provided separately or in sub-combinations for co-administration.
- the EFAs may sometimes be conveniently given as a general dietary supplement, and possibly the zinc as well if used, the selenium being administered under more direct medical supervision.
- Bioavailable forms of zinc for example zinc gluconate and zinc sulphate, are well known and amounts may for example be 1 to 800 mg/day, preferably 2.5 to 800 mg/day, more preferably 5 to 80 mg/day (elemental zinc basis).
- the acids may be used as such or as pharmaceutically acceptable and physiologically equivalent derivatives as, for example, detailed later herein for GLA and DGLA, and reference to any of the acids is to be taken as including reference to the acids when in the form of such derivatives. Equivalence is demonstrated by entry into the pathway quoted herein, as evidenced by effects corresponding to those of the acids themselves or their natural glyceride esters.
- the method is suitably that plasma samples (1 ml) are extracted with chloroform:methanol (2: 1). The extract is filtered through sodium sulphate, evaporated to dryness, and taken up in 0.5 ml chloroform: methanol. The lipid fractions are separated by thin layer chromatography or silica gel plates. The phospholipid fraction, taken to reflect essential fatty acid contents most sensitively, is methylated using boron trifluoride-methanol. The resulting methyl esters of the fatty acids are separated and measured using a Hewlett-Packard 5880 gas chromatograph with a six foot column packed with 10% silar on chromosorb WAW 106/230. The carrier gas is helium (30 ml/min).
- Oven temperature is programmed to rise from 165°C to 190°C at 2°C/min.
- Detector temperature is 220°C and injector temperature 200°C.
- Retention times and peak areas are automatically computed by Hewlett-Packard Level 4 integrator. Peaks are identified by comparison with standard fatty acid methyl esters.
- the invention is chiefly described in terms of methods of treatment and pharmaceutical compositions, but it will be understood that the gamma-linolenic and other EFAs, being in the nature of dietary supplements, can be incorporated in a dietary margarine or other foodstuff and such are to be understood as within the term pharmaceutical composition when for the purposes set out.
- Convenient physiologically equivalent derivatives of GLA and DGLA for use according to the invention as with the other essential fatty acids include salts, amides, esters including glyceride esters and alkyl (e.g. C1 to C4) esters, and phospholipids.
- compositions may be produced for use in the invention by associating the natural or synthetic acids, as such or as derivatives, with an acceptable pharmaceutical vehicle. It is, however, at present convenient to provide at least the GLA in the form of an available oil having a high GLA content, hence reference to "oil" herein.
- oils currently available is the seed of evening primrose species such as Oenothera biennis L. and Oenothera lamarckiana , the oil extract therefrom containing about 8% GLA and about 72% linoleic acid in the form of their glycerides, together with other glycerides (percentages based on total fatty acids).
- GLA is borage species such as Borago officinalis which, though current yield per acre is low, provide a richer source than Oenothera oil. Oils from the seeds of members of the Ribes family are also often rich in GLA. Recent studies on fungi which can be cultivated by fermentation promise a fungal oil source.
- the oil is extracted from the seed by one of the conventional methods of extraction such as cold pressure, screw pressure after partially cooking the seed, or solvent extraction.
- seed oil extracts referred to above can be used as such or can, for example, if desired, be fractionated to yield an oily composition containing the triglycerides of gamma-linolenic and linoleic acids as the main fatty acid components, the gamma-linolenic acid content being, if desired, a major proportion. Seed oil extracts appear to have a stabilising effect upon DGLA if present.
- DGLA can be prepared by chemical synthesis or by fungal fermentation.
- n-3 acids are available from marine oils, particularly the 20:5 n-3 and 22:6 n-3 acids, and recently from microbial fermentation.
- the acids can be isolated from these sources by, for example, saponification under mild non-oxidising conditions followed by preparative gas liquid chromatography. Synthesis of the acids is difficult but not impossible and provides another source.
- compositions are conveniently in a form suitable for oral, rectal or parenteral administration in a suitable pharmaceutical vehicle, as discussed in detail, for example, in Williams British Patent Specification No. 1,082,624, to which reference may be made, and in any case very well known generally for any particular kind of preparation.
- tablets, capsules, ingestible liquid or powder preparations can be prepared as required, and topical preparations also when the gamma-linolenic acid or other acids are absorbed through the skin.
- Injectable solutions of hydrolysed Oenothera oil may be prepared using albumin to solubilise the free acid.
- a preservative is incorporated into the preparation.
- Alpha-tocopherol in concentration of about 0.1% by weight has been found suitable for the purpose, and there are other stabilisers such as ascorbyl palmitate or stearate, all well known in the field.
- any dosage unit should not exceed that appropriate to the rate and manner of administration to be employed but on the other hand should also desirably be adequate to allow the desired rate of administration to be achieved by a small number of doses.
- the rate of administration will moreover depend on the precise pharmacological action desired.
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Abstract
Description
- The invention relates to pharmaceutical compositions of essential fatty acids (EFAs) and treatment of disease therewith.
- Dementia and depression are common psychiatric disorders. They frequently occur together in the same patient.
- While there are many drugs which treat depression, not all patients respond. Moreover, most of these drugs have important side effects which limit their usefulness. There is therefore a need for new, safe treatments for depression.
- Dementia can be caused by a variety of underlying disorders, the most important being Alzheimer's disease, multi-infarct dementia, and infections with certain viruses or virus-like agents. The cause of Alzheimer's disease is unknown but there is loss of nerve cells in key areas of the brain. In multi-infarct dementia, cell death follows reduced oxygen and blood flow as a consequence of multiple blockages of small arteries. There are no known satisfactory treatments for dementia of any type.
-
- The above pathways are not normally reversible nor, in man, are n-3 and n-6 series acids interconvertible.
- The acids, which in nature are of the all-cis configuration, are systematically named as derivatives of the corresponding octadecanoic, eicosanoic or docosanoic acids, e.g. delta-9,12-octadecadienoic acid or delta-4,7,10,13,16,19-docosahexaenoic acid, but numerical designations such as, correspondingly, 18:2 n-6 or 22: 6 n-3 are convenient. Initials, for example, EPA for the 20:5 n-3 acid (eicosapentaenoic acid) or DHA for the 22:6 n-3 acid (docosahexaenoic acid), are also used but do not serve when n-3 and n-6 acids of the same chain length and degree of unsaturation exist as for example with the 22:5 acids. Trivial names in more or less common use in the n-6 series are as shown. Of the n-3 series only 18:3 n-3 has a commonly used trivial name, alpha-linolenic acid, though the name stearidonic acid is coming into use for the 18:4 n-3 acid and the names eicosapentaenoic acid and docosahexanenoic acid as such are also used. The alpha isomer of linolenic acid was characterised earlier than gamma-linolenic acid and reference in the literature simply to linolenic acid, especially in the earlier literature, is to the alpha-acid.
- The cell membranes of nerve cells in the brain are rich in EFAs derived as above from dietary linoleic acid (LA) and alpha-linolenic acid (ALA). Unlike other tissues of the body, the brain contains very little linoleic acid and alpha-linolenic acid: almost all its EFAs are in the form of derivatives of the dietary acids arising from initial 6-desaturation, and are required for normal membrane structure and normal function. Since the 6-desaturation of linoleic acid and alpha-linolenic acid is a slow, rate-limiting step which can be interfered with by many factors, administration of these acids is not a good way to elevate brain EFA levels. It is better for such a purpose to administer acids such as gamma-linolenic acid (GLA) and dihomo-gamma-linolenic acid (DGLA) of the n-6 family, and stearidonic acid (18:4 n-3), eicosapentaenoic acid (EPA) and docosa-hexaenoic acid (DHA) of the n-3 family. These acids are often referred to as "6-desaturated" EFAs, a loose but convenient term for the acids arising in the body by the pathways detailed above and involving the initial 6-desaturation of the dietary acid.
- Since the cell membranes of the brain are so rich in 6-desaturated EFAs it seemed worthwhile, in initial work that has led to this invention, to test their effects in dementia and depression. We therefore performed a study in thirty patients with dementia of the Alzheimer type (twenty three female, seven male, average age 78 years). They were examined by several standard tests, including the anomalous sentences repetition test (ASRT), the coloured progressive matrices test (CPMT), the graded naming test (GNT), the digit copying test (DCT) and the Hamilton Depression Rating Scale (HDRS). The first four tests are widely used to measure dementia, while the Hamilton scale is the most widely used measure of depression.
- Half the patients were given gamma-linolenic acid (GLA) in the form of evening primrose oil (6 g/day containing about 500 mg of GLA), equivalent to giving DGLA as conversion is very rapid in the human body. These patients were also given zinc sulphate (200 mg/day) and sodium selenite (2 mg/day) each mg containing about 457 microg elemental selenium). The other half of the patients were given placebo corresponding to the GLA, zinc and selenium.
- The significance of zinc is that it is known to potentiate some actions of GLA (EP-A-0,003,407, US-A-4,273,763). However, in a previous study in long stay psychiatric patients, GLA alone or in combination with zinc failed to improve depression and had only a small effect on memory although it did improve the schizophrenic features of psychosis (Horrobin and Vaddadi, unpublished results). Zinc alone therefore does not synergise with GLA in treatment of dementia or depression. The inventors then decided to add selenium to the treatment regime in the study, the rationale being that EFAs are highly susceptible to oxidation and can be easily destroyed. Selenium can inhibit the oxidation of EFAs and also, as a component of the enzyme glutathione peroxidase, help to eliminate any harmful peroxides which may be formed by EFA oxidation. There are therefore strong reasons for combining GLA and DGLA and selenium. The GLA and/or DGLA will raise the levels of the appropriate EFAs at important sites in the body: the selenium will inhibit the oxidation of these important compounds and will also help to remove any oxidation products which happen to be formed. This inter-action between GLA/DGLA and selenium is in no way dependent on the presence of zinc and will occur entirely independently of zinc. Zinc may improve the responses to GLA and selenium even further by increasing the availability of the GLA or DGLA.
- In the trials, the patients were randomly allocated to the active and placebo groups and the trial was conducted on a double-blind basis. The patients were treated for twenty weeks and the tests were performed before treatment started and at the end of treatment.
- After twenty weeks there were no significant changes in the placebo group, whose scores remained close to baseline values. The results in the active group are shown in Table 2. It appears that selenium can greatly enhance the effect of GLA on both the dementia and the depression, improvements that are remarkable in a disease that is currently regarded as intractable. Moreover, the effects were achieved without producing any important side effects. In the table it should be noted that changes in scores are given, for the patients treated with GLA and zinc plus selenium. The change from baseline to the end of the trial was assessed statistically by the Wilcoxon non-parametric test. For the ASRT, CPMT, GNT and DCT, an increase in score represents an improvement. For the HDRS a decrease in score represents an improvement.
- From the above, the invention in its various aspects lies in:-
- 1. As such or when for use in therapy, particularly of dementia and/or depression, a pharmaceutical composition of GLA or DGLA with a form of selenium which is bioavailable, optionally also with an 18:4 or higher n-3 EFA (notably 18:4, 20:5, 22:5, 22:6) and/or bioavailable zinc.
- 2. A method of preparation of a medicament for use in curative or prophylactic therapy against dementia, depression or both, characterised in that said medicament comprises GLA or DGLA for use with bioavailable selenium, or bioavailable selenium for use with GLA or DGLA, or both said GLA and DGLA and said selenium, said medicament optionally in each case comprising also and n-3 EFA and/or zinc as set out at 1. above.
- The composition according to the invention may be used in the treatment or prevention of dementia and/or depression.
- The GLA or DGLA may be used at 1 mg to 20 g/day, preferably 50 mg to 4 g and very preferably 200 mg to 2 g. Like amounts of n-3 EFAs, where present, may be used. GLA can be synthesised but it is usually derived from natural oils such as those of the evening primrose, blackcurrant or borage, or the storage oils of various fungi. GLA and other EFAs can be administered in any biologically assimilable form, such as the free acid, salt, ester, amide, phospholipid or natural or synthetic tri-glycerides. It can be administered in any convenient way, eg. orally, parenterally, topically or rectally, as can the compositions as a whole. DGLA as such is not readily available, but fungal sources are known and chemical synthesis is possible; amounts for administration are as for GLA.
- The selenium may be used at 1 to 10,000 microg per day, (elemental selenium basis) preferably 50 to 2000 microg/day, very preferably 200 to 1000 microg/ day. The selenium too can be administered in any convenient way, i.e. orally, parenterally, rectally or topically in any biologically assimilable form. Possible forms include sodium selenite, selenious acid, selenomethionine and selenium yeast (yeast grown in a bioavailable selenium containing environment).
- The GLA and selenium, and the zinc and n-3 EFAs when used, may be incorporated in the same formulation for ease of administration or may be provided separately or in sub-combinations for co-administration. In particular the EFAs may sometimes be conveniently given as a general dietary supplement, and possibly the zinc as well if used, the selenium being administered under more direct medical supervision.
- Bioavailable forms of zinc, for example zinc gluconate and zinc sulphate, are well known and amounts may for example be 1 to 800 mg/day, preferably 2.5 to 800 mg/day, more preferably 5 to 80 mg/day (elemental zinc basis).
- As indicated above, the acids may be used as such or as pharmaceutically acceptable and physiologically equivalent derivatives as, for example, detailed later herein for GLA and DGLA, and reference to any of the acids is to be taken as including reference to the acids when in the form of such derivatives. Equivalence is demonstrated by entry into the pathway quoted herein, as evidenced by effects corresponding to those of the acids themselves or their natural glyceride esters. Thus, indirect identification of useful derivatives is by their having the valuable effect in the body of the acid itself, but conversion can be shown directly by gas chromatographic analysis of concentrations in blood, body fat, or other tissue by standard techniques, for example those of Pelick et al, page 23, "Analysis of Lipids and Lipoproteins" Ed Perkins, American Oil Chemists Society, Champaign, Illinois, U.S.A.
- In outline the method is suitably that plasma samples (1 ml) are extracted with chloroform:methanol (2: 1). The extract is filtered through sodium sulphate, evaporated to dryness, and taken up in 0.5 ml chloroform: methanol. The lipid fractions are separated by thin layer chromatography or silica gel plates. The phospholipid fraction, taken to reflect essential fatty acid contents most sensitively, is methylated using boron trifluoride-methanol. The resulting methyl esters of the fatty acids are separated and measured using a Hewlett-Packard 5880 gas chromatograph with a six foot column packed with 10% silar on chromosorb WAW 106/230. The carrier gas is helium (30 ml/min). Oven temperature is programmed to rise from 165°C to 190°C at 2°C/min. Detector temperature is 220°C and injector temperature 200°C. Retention times and peak areas are automatically computed by Hewlett-Packard Level 4 integrator. Peaks are identified by comparison with standard fatty acid methyl esters.
- The invention is chiefly described in terms of methods of treatment and pharmaceutical compositions, but it will be understood that the gamma-linolenic and other EFAs, being in the nature of dietary supplements, can be incorporated in a dietary margarine or other foodstuff and such are to be understood as within the term pharmaceutical composition when for the purposes set out.
- Convenient physiologically equivalent derivatives of GLA and DGLA for use according to the invention as with the other essential fatty acids, include salts, amides, esters including glyceride esters and alkyl (e.g. C₁ to C₄) esters, and phospholipids.
- If desired, pharmaceutical compositions may be produced for use in the invention by associating the natural or synthetic acids, as such or as derivatives, with an acceptable pharmaceutical vehicle. It is, however, at present convenient to provide at least the GLA in the form of an available oil having a high GLA content, hence reference to "oil" herein.
- One source of oils currently available is the seed of evening primrose species such as Oenothera biennis L. and Oenothera lamarckiana, the oil extract therefrom containing about 8% GLA and about 72% linoleic acid in the form of their glycerides, together with other glycerides (percentages based on total fatty acids). Other sources of GLA are borage species such as Borago officinalis which, though current yield per acre is low, provide a richer source than Oenothera oil. Oils from the seeds of members of the Ribes family are also often rich in GLA. Recent studies on fungi which can be cultivated by fermentation promise a fungal oil source.
- The oil is extracted from the seed by one of the conventional methods of extraction such as cold pressure, screw pressure after partially cooking the seed, or solvent extraction.
- Fractionation of a typical sample of this oil in the form of methyl esters shows the relative proportions:
- Palmitate
- 6.15
- Stearate
- 1.6
- Oleate
- 10.15
- Linoleate
- 72.6
- Gamma-linolenate
- 8.9
- The seed oil extracts referred to above can be used as such or can, for example, if desired, be fractionated to yield an oily composition containing the triglycerides of gamma-linolenic and linoleic acids as the main fatty acid components, the gamma-linolenic acid content being, if desired, a major proportion. Seed oil extracts appear to have a stabilising effect upon DGLA if present.
- DGLA can be prepared by chemical synthesis or by fungal fermentation.
- The n-3 acids are available from marine oils, particularly the 20:5 n-3 and 22:6 n-3 acids, and recently from microbial fermentation.
- The acids can be isolated from these sources by, for example, saponification under mild non-oxidising conditions followed by preparative gas liquid chromatography. Synthesis of the acids is difficult but not impossible and provides another source.
- As mentioned briefly above, the compositions are conveniently in a form suitable for oral, rectal or parenteral administration in a suitable pharmaceutical vehicle, as discussed in detail, for example, in Williams British Patent Specification No. 1,082,624, to which reference may be made, and in any case very well known generally for any particular kind of preparation. Thus, for example, tablets, capsules, ingestible liquid or powder preparations can be prepared as required, and topical preparations also when the gamma-linolenic acid or other acids are absorbed through the skin. Injectable solutions of hydrolysed Oenothera oil may be prepared using albumin to solubilise the free acid.
- Advantageously, a preservative is incorporated into the preparation. Alpha-tocopherol in concentration of about 0.1% by weight has been found suitable for the purpose, and there are other stabilisers such as ascorbyl palmitate or stearate, all well known in the field.
- It will be understood that the absolute quantity of active materials present in any dosage unit should not exceed that appropriate to the rate and manner of administration to be employed but on the other hand should also desirably be adequate to allow the desired rate of administration to be achieved by a small number of doses. The rate of administration will moreover depend on the precise pharmacological action desired.
- Dementia and depression, occurring separately or together, are treated with the following:-
- 1. Soft gelatin capsules containing 500 mg evening primrose oil (EPO, 40 to 45 mg GLA) and 0.1 mg sodium selenite, 12 caps/day.
- 2. Soft gelatin capsules containing 500 mg EPO, 0.1 mg sodium selenite, 100 mg fish oil (containing 20 mg of EPA and 8 mg of DHA), and 10 mg of zinc gluconate, 10 caps/day.
- 3. Hard gelatin capsules containing 200 mg of purified GLA or DGLA and seleno-methionine or selenium yeast containing 100 microg elemental selenium, 6 caps/day.
- 4. A syrup containing in each 5 ml (teaspoonful) 250 mg GLA and 200 microg selenium in the form of selenomethionine, 6 tsp/day.
- 5. A foam whip containing in each 5ml 300 mg of DGLA and 150 microg selenium in the form of selenium yeast, taken correspondingly to Example 4 at 6 x 5 ml/day.
- 6. A fluid for parenteral administeration containing in each 5 ml 500 mg of GHLA and 500 microg of elemental selenium in the form of sodium selenite, 5 ml given daily.
- 7. A topical formulation containing 100 mg/ml GLA and 100 microg/ml selenium in the form of seleno-methionine, 10 ml applied daily.
- 8. Soft gelatin capsules containing 200 mg DGLA, 50 mg DHA, 200 microg sodium selenite and 30 mg zinc gluconate, 6 cap/day.
- 9. Soft gelatin capsules containing 400 mg GLA, 50 mg stearidonic acid, 30 mg zinc sulphate and 200 microg selenium as selenium yeast, 4 caps/day.
Claims (5)
- A method of preparation of a medicament for use in curative or prophylactic therapy against dementia, depression or both, characterised in that said method comprises bringing into association gamma-linolenic and (GLA) or dihomo-gamma-linolenic acid (DGLA) and bioavailable selenium.
- A method according to claim 1, wherein the GLA or DGLA and the bioavailable selenium are presented separately.
- A method according to claims 1 or 2, wherein the medicament further comprises an 18:4 or higher n-3 EFA and/or bioavailable zinc.
- A method according to any of claims 1 to 3, wherein the medicament contains per dose the following amounts of the components or sub-multiples thereof, namely:(i) the or each fatty acid, 1 mg to 20 g, preferably 50 mg to 4g, and very preferably 200 mg to 2 g;(ii) the bioavailable selenium, 1 to 10,000 µg, preferably 50 to 2,000 µg, and very preferably 200 to 1,000 µg:(iii) the bioavailable zinc, where present, 1 to 800 mg, preferably 2.5 to 800 mg, more preferably 5 to 80 mg.
- A method according to claim 1 wherein the medicament is prepared for daily administration of amount(s) of active materials as set out at (i) and/or (ii) and/or (iii) in claim 4.
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US8633248B2 (en) | 2005-06-27 | 2014-01-21 | Agresearch Limited | Parenteral selenomethionine for production of selenium-rich foods |
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US20060292217A1 (en) * | 2005-06-03 | 2006-12-28 | Schmidt Robbin D | Nutritional supplement and soft gelatin capsule delivery system |
US8871715B2 (en) * | 2005-10-14 | 2014-10-28 | Alltech, Inc. | Use of selenium compounds, especially selenium yeasts for altering cognitive function |
US8865763B2 (en) * | 2005-10-14 | 2014-10-21 | Alltech, Inc. | Methods and compositions for altering cell function |
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US20100247679A1 (en) * | 2006-04-24 | 2010-09-30 | Alltech, Inc. | Methods and compositions for altering cell function |
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US8715648B2 (en) | 2011-02-16 | 2014-05-06 | Pivotal Therapeutics Inc. | Method for treating obesity with anti-obesity formulations and omega 3 fatty acids for the reduction of body weight in cardiovascular disease patients (CVD) and diabetics |
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GB1082624A (en) | 1965-02-26 | 1967-09-06 | Calmic Ltd | Improvements in or relating to therapeutically active compounds |
US4273763A (en) * | 1978-01-23 | 1981-06-16 | Efamol Limited | Pharmaceutical and dietary compositions |
IE47777B1 (en) | 1978-01-23 | 1984-06-13 | Efamol Ltd | Pharmaceutical and dietary composition comprising gamma-linolenic acids |
HU204199B (en) * | 1987-03-18 | 1991-12-30 | Caola Kozmetikai | Process for producing pharmaceutical compositions containing unsaturated fatty acids and selenium as active components |
DE3778360D1 (en) * | 1987-07-09 | 1992-05-21 | Pierre Moreau | OLIGO ELEMENTS RICH COMPOSITIONS AND THEIR PRODUCTION PROCESS. |
-
1990
- 1990-01-18 GB GB909001121A patent/GB9001121D0/en active Pending
-
1991
- 1991-01-08 IE IE5091A patent/IE67622B1/en not_active IP Right Cessation
- 1991-01-09 CA CA002033823A patent/CA2033823C/en not_active Expired - Fee Related
- 1991-01-09 US US07/638,998 patent/US5116624A/en not_active Expired - Lifetime
- 1991-01-09 ZA ZA91183A patent/ZA91183B/en unknown
- 1991-01-10 AU AU69256/91A patent/AU638525B2/en not_active Ceased
- 1991-01-11 NZ NZ236744A patent/NZ236744A/en unknown
- 1991-01-14 ES ES91300234T patent/ES2060290T3/en not_active Expired - Lifetime
- 1991-01-14 DE DE91300234T patent/DE69100724T2/en not_active Expired - Fee Related
- 1991-01-14 EP EP91300234A patent/EP0440341B1/en not_active Expired - Lifetime
- 1991-01-14 DK DK91300234.1T patent/DK0440341T3/en active
- 1991-01-14 AT AT91300234T patent/ATE98125T1/en not_active IP Right Cessation
- 1991-01-17 JP JP3003937A patent/JP3008213B2/en not_active Expired - Fee Related
-
1994
- 1994-07-28 HK HK74994A patent/HK74994A/en not_active IP Right Cessation
Non-Patent Citations (1)
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---|---|---|---|---|
US8633248B2 (en) | 2005-06-27 | 2014-01-21 | Agresearch Limited | Parenteral selenomethionine for production of selenium-rich foods |
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JP3008213B2 (en) | 2000-02-14 |
IE67622B1 (en) | 1996-04-17 |
HK74994A (en) | 1994-08-05 |
CA2033823A1 (en) | 1991-07-19 |
DK0440341T3 (en) | 1994-02-14 |
US5116624A (en) | 1992-05-26 |
JPH0733655A (en) | 1995-02-03 |
IE910050A1 (en) | 1991-07-31 |
ATE98125T1 (en) | 1993-12-15 |
AU6925691A (en) | 1991-07-25 |
AU638525B2 (en) | 1993-07-01 |
GB9001121D0 (en) | 1990-03-21 |
ZA91183B (en) | 1991-10-30 |
CA2033823C (en) | 2002-04-09 |
DE69100724D1 (en) | 1994-01-20 |
DE69100724T2 (en) | 1994-04-28 |
ES2060290T3 (en) | 1994-11-16 |
NZ236744A (en) | 1993-03-26 |
EP0440341A1 (en) | 1991-08-07 |
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